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Rituximab Hyaluronidase in Combination with Chemotherapy in Treating Aggressive B-cell Lymphoma in Uganda

Trial Status: Active

This phase I trial studies how well rituximab hyaluronidase and combination chemotherapy work in treating patients in Uganda with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus associated multicentric Castleman disease. Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a molecule called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Hyaluronidase allows rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by injection under the skin is faster than giving rituximab alone by infusion into the blood. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, methotrexate, etoposide, doxorubicin, and prednisone work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. While rituximab has a clear survival benefit in patients within developed countries, differences in supportive care and infectious co-morbidities require special attention. Giving rituximab hyaluronidase alone or in combination with chemotherapy may work better in treating patients with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus associated multicentric Castleman disease compared to chemotherapy alone in Uganda.

Inclusion Criteria

  • Histology and immunohistochemistry (CD20+) confirmed Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), or histology confirmed KSHV-associated multicentric Castleman disease with elevated blood KSHV viral load
  • Cohort 1: Age should be equal to or greater than 15
  • Cohort 2: Age: 2-15
  • Measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Able to provide informed consent (adults) or assent (children < 18 years) in English or Luganda
  • Human immunodeficiency virus (HIV)-infected patients eligible if meet the following criteria: * CD4+ T-cell count > 200 cells/uL * HIV treatable with effective antiretroviral therapy that does not include agents with known significant drug-drug interactions with accompanying chemotherapy (ritonavir and cobicistat contraindicated)

Exclusion Criteria

  • Previous therapy for lymphoma or KSHV-multicentric Castleman disease (MCD)
  • History of hypersensitivity to rituximab
  • Pregnant or nursing women. Men or women may not participate unless they have agreed to use effective contraception during treatment and for 12 months following completion of therapy
  • Inadequate organ function, unless attributed to lymphoma or KSHV-MCD
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 times upper limit of normal
  • Creatinine > 2 times upper limit than normal or calculated creatinine clearance < 60 mL/min
  • New York Heart Association (NYHA) cardiac failure class III or IV
  • Patients with clinically significant anemia-hemoglobin less than 10 g/dL
  • Central nervous system (CNS) masses consistent with lymphoma or untreated infection; leptomeningeal disease will not be excluded
  • Patients with malignancy within 5 years, other than resected local skin cancer or limited Kaposi sarcoma (KS) (no known pulmonary KS)
  • Patients with evidence of active infections including malaria and hepatitis B (participants with hepatitis B virus [HBV] controlled on antivirals will not be excluded)

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE
Contact: Thomas S. Uldrick
Phone: 206-667-7485

PRIMARY OBJECTIVES:

I. To evaluate the safety of subcutaneous rituximab and hyaluronidase human (rituximab hyaluronidase) in pediatric and adult participants with Burkitt lymphoma, diffuse large B-cell lymphoma, or Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease in Uganda when administered with standard chemotherapy and site-specific supportive care.

II. To evaluate weight-based dosing of subcutaneous rituximab hyaluronidase that minimizes extreme dose levels in pediatrics, defined as a Ctrough level below 25 ug/ml or above 400 ug/ml after the first subcutaneous dose.

SECONDARY OBJECTIVES:

I. To estimate response rates at the end of therapy.

II. To estimate overall survival, progression-free survival and disease-free survival at 1 year from initiation of therapy.

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of age, weight, dose, dosing schedule and lactate dehydrogenase (LDH) on rituximab Ctrough in pediatrics and adults.

II. Evaluate gut microbiome at baseline, end of therapy, six months follow up visit and one year follow up visit, and explore associations of microbiome diversity and other characteristics with clinical parameters such as human immunodeficiency virus (HIV) infection status.

III. Evaluate KSHV and Epstein-Barr virus (EBV) viral load at baseline, end of therapy, six months follow up and one year follow up, and explore associations with clinical parameters.

IV. To compare response rate and survival to similar historical cohorts.

V. Explore the molecular characteristics of baseline tumors and their relationship to clinical parameters such as

complete response rate and overall survival.

VI. To bank blood, rectal swab and tissue specimens as well as data for future exploratory correlative studies.

OUTLINE: Open-label Phase I study characterizing the safety, tolerability, and activity of subcutaneous rituximab hyaluronidase (sqR) alone (KSHV-MCD), or combined with local standard of care chemotherapy (BL or DLBCL), in 2 age-based cohorts of patients:

1) Cohort 1: Age >= 15

2) Cohort 2: Age: 2-14

sqR dose for Cohort 1 (adults) will be 1400 mg (flat dose); sqR dose for Cohort 2 (pediatrics) will depend on patient weight: >= 35 kg: 1400 mg, < 35 kg: 700 mg. For all participants, sqR will be administered with local standard of care chemotherapy (BL, DLBCL) or alone (KSHV-MCD), and supportive care.

Each cohort comprises two Therapy Groups. Therapy Group 1: up to 6 participants and will receive the first cycle of rituximab IV, and subsequent cycles as flat-dose sqR. Therapy Group 2: up to 12 participants and will receive flat-dose sqR for all cycles.

Disease-specific chemotherapy to be administered with rituximab hyaluronidase include:

PEDIATRIC BURKITT LYMPHOMA (BL): cyclophosphamide, vincristine and prednisone followed by 6 cycles of cyclophosphamide, vincristine, and methotrexate (COP-COM).

DLBCL: 6 cycles of cyclophosphamide, doxorubicin, vincristine and prednisone PO on days 1-5 of cycle 1 (CHOP).

ADULT BL: 6 cycles modified dose: etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone PO on days 1-5 (adjusted EPOCH).

KSHV-MCD: Rituximab or rituximab hyaluronidase SC on days 1, 8, 15, and 22.

After completion of study treatment, patients are followed up at 30 days, 3, 6, 9 and 12 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Fred Hutch / University of Washington Cancer Consortium

Principal Investigator
Thomas S. Uldrick

  • Primary ID RG1001799
  • Secondary IDs NCI-2019-01493, U028, 10040
  • Clinicaltrials.gov ID NCT03864419